TY - JOUR
T1 - Feedback regulation of T cell development
T2 - Manifestations in aging
AU - Mehr, Ramit
AU - Perelson, Alan S.
AU - Fridkis-Hareli, Masha
AU - Globerson, Amiela
N1 - Funding Information:
We are much obliged to Professor Lee Segel for many helpful discussions. Simulationsw ere performedu sing ‘GRIND’ software (Copyright R.J. De Boer, 1983).T his work was performed under the auspiceso f the US Departmento f Energy and supportedb y NIH grant A128433;t he US-Israel Binational Science Foundation Grant No. 92-00171a; grantf rom the Brookdale Instituteo f Gerontol- ogy and Adult Human Developmenti n Israel, and Eshel Association for the Planning and Developmento f Servicesf or the Aged in Israel; and the Santa Fe Institute through a Joseph P. and Jeanne M. Sullivan Foundation grant to their TheoreticalI mmunology program.
PY - 1996/11/13
Y1 - 1996/11/13
N2 - Recent findings have indicated that mature T cells may regulate thymocytopoiesis in an age-related differential manner. The studies were based on T lymphocyte development in mouse fetal thymus stroma colonized with immature thymocytes and CD4+ T cells from young or old donors. In the present study, we used mathematical modeling and computer simulations in order to identify the thymocyte subsets that are the targets for this type of regulation, and the processes affected by it. Our results suggest that thymocyte development is subject to regulation through 2 feedback loops: mature CD4+ cells exert a negative feedback on the double-negative to double-positive transition and on double-positive subset growth, and a positive feedback on the double-positive to CD4 single-positive transition. These effects may operate, in young mice, through a reduction in the rate of death of CD4+8- thymocytes, and a faster maturation of double-positive cells. In old mice, our simulations suggest that there may additionally be a reduction in double-positive proliferation rate. In some, but not all, of the simulations of old donor-derived thymocytes, we also had to assume a reduction in double-negative to double-positive differentiation, an increase in double-positive death rates, an increase of CD4+8- cell division rate, and a decrease of differentiation to the CD8 lineage.
AB - Recent findings have indicated that mature T cells may regulate thymocytopoiesis in an age-related differential manner. The studies were based on T lymphocyte development in mouse fetal thymus stroma colonized with immature thymocytes and CD4+ T cells from young or old donors. In the present study, we used mathematical modeling and computer simulations in order to identify the thymocyte subsets that are the targets for this type of regulation, and the processes affected by it. Our results suggest that thymocyte development is subject to regulation through 2 feedback loops: mature CD4+ cells exert a negative feedback on the double-negative to double-positive transition and on double-positive subset growth, and a positive feedback on the double-positive to CD4 single-positive transition. These effects may operate, in young mice, through a reduction in the rate of death of CD4+8- thymocytes, and a faster maturation of double-positive cells. In old mice, our simulations suggest that there may additionally be a reduction in double-positive proliferation rate. In some, but not all, of the simulations of old donor-derived thymocytes, we also had to assume a reduction in double-negative to double-positive differentiation, an increase in double-positive death rates, an increase of CD4+8- cell division rate, and a decrease of differentiation to the CD8 lineage.
KW - Aging
KW - Mathematical model
KW - T cell development
KW - Thymus
UR - http://www.scopus.com/inward/record.url?scp=0030582545&partnerID=8YFLogxK
U2 - 10.1016/S0047-6374(96)01787-3
DO - 10.1016/S0047-6374(96)01787-3
M3 - Article
AN - SCOPUS:0030582545
SN - 0047-6374
VL - 91
SP - 195
EP - 210
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
IS - 3
ER -